Field of the Invention
The present invention relates to optical resonators and, more specifically, to biomedical and chemical sensing using optical resonators.
Brief Description of the Related Art
Resonators play a very important role in RF (radio frequency), microwave and electronic systems and are poised to play an equally important role in optics and photonics. Recently, it has been shown that optical resonators are particularly sensitive for detection of chemicals, biochemicals and virus nanoparticles. See, for example, Vollmer, F., D. Braun, et al., “Protein detection by optical shift of a resonant microcavity,” Applied Physics Letters 80(21): 3 (2002); Arnold, S., M. Khoshsima, et al., “Shift of whispering-gallery modes in microspheres by protein adsorption,” Optics Letters 28(4): 3 (2003); Teraoka, I., S. Arnold, et al., “Perturbation approach to resonance shifts of whispering-gallery modes in a dielectric microsphere as a probe of a surrounding medium,” Journal of the Optical Society of America B-Optical Physics 20(9): 1937-1946 (2003); Vollmer, F., S. Arnold, et al., “Multiplexed DNA quantification by spectroscopic shift of two microsphere cavities,” Biophysical Journal 85(3): 6 (2003); and Vollmer, F., S. Arnold, et al., “Single Virus Detection from the Reactive Shift of a Whispering-Gallery Mode,” Proc. Nat'l Acad. Sci. U.S.A. 105(52): 5 (2008). The detection principle is based on the exposure of the resonator (cavity) to the sample. This can be achieved either by directly introducing the sample in the optical cavity (Vollmer, F. and P. Fischer, “Ring-resonator-based frequency-domain optical activity measurements of a chiral liquid,” Optics Letters 31(4): 453-455 (2006) and Loncar, M., B. G. Lee, et al., “Design and fabrication of photonic crystal quantum cascade lasers for optofluidics,” Optics Express 15(8): 4499-4514 (2007)), or alternatively by adsorbing the chemical to the cavity boundary (surface)(see, Vollmer, F., D. Braun, et al., “Protein detection by optical shift of a resonant microcavity,” Applied Physics Letters 80(21): 3 (2002)) or, as a third alternative, by immersing the cavity in a bulk sample (see, Teraoka, I., S. Arnold, et al., “Perturbation approach to resonance shifts of whispering-gallery modes in a dielectric microsphere as a probe of a surrounding medium,” Journal of the Optical Society of America B-Optical Physics 20(9): 1937-1946 (2003) and Loncar, M., A. Scherer, et al., “Photonic crystal laser sources for chemical detection,” Applied Physics Letters 82: 4648(2003)). The presence of the sample, quantity and optical properties can be determined from a change of one or more characteristic resonator parameters such as resonance wavelength and intensity.
Also, it recently has been shown that optical resonators can be defined in 1D photonic crystal type resonators. The photonic crystal platform enables strong localization of photons to sub-wavelength volumes for long periods of time, provides means to control optical signals at single-photon level. This progress in nanophotonics has been paralleled with progress in the field of nanoscale electro-mechanical systems (NEMS) and realization of ultra-sensitive mass sensors capable of detecting single-molecules.
The present invention relates to the broader field of high-throughput (HT) biosensing, i.e. the detection and characterization of biological material for toxicology, genomics and proteomics. With genomes of many species completed, a revolution in genetic and proteomic analysis has begun. Technological advances of recent years have made this revolution possible by replacing labor-intensive, traditional biochemical methods with automated nucleic acid and protein analysis techniques. See, for example, Marshall, A. and J. Hodgson, “DNA chips: An array of possibilities,” Nature Biotechnology 16(1): 27-31 (1998); Schena, M., R. A. Heller, et al., “Microarrays: biotechnology's discovery platform for functional genomics,” Trends in Biotechnology 16(7): 301-306 (1998); Jaklevic, J. M., H. R. Garner, et al., “Instrumentation for the genome project,” Annual Review of Biomedical Engineering 1: 649-678 (1999); and Nuwaysir, E. F., M. Bittner, et al., “Microarrays and toxicology: The advent of toxicogenomics,” Molecular Carcinogenesis 24(3): 153-159 (1999). To exploit the vast amount of genetic and proteomic information for medical diagnostic purposes, drug discovery, food testing, forensic sciences, and environmental monitoring, it is necessary to further miniaturize and integrate DNA/RNA and protein analysis techniques into robust and easy to manufacture lab-on-a-chip and micro total analysis systems. See, Heller, M. J., “DNA microarray technology: Devices, systems, and applications,” Annual Review of Biomedical Engineering 4: 129-153 (2002); Santacroce, R., A. Ratti, et al., “Analysis of clinically relevant single-nucleotide polymorphisms by use of microelectronic array technology,” Clinical Chemistry 48(12): 2124-2130 (2002); Simon, R., M. D. Radmacher, et al., “Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification,” Journal of the National Cancer Institute 95(1): 14-18 (2003); Smyth, G. K. and T. Speed, “Normalization of cDNA microarray data,” Methods 31(4): 265-273 (2003); and Yanaihara, N., N. Caplen, et al., “Unique microRNA molecular profiles in lung cancer diagnosis and prognosis,” Cancer Cell 9(3): 189-198 (2006). Gene chips provide such a means for high-throughput DNA screening using oligonucleotide arrays.
Commercially available protein- and gene ‘chips’ quantitate the fluorescence intensity of labeled biomarkers after binding to specific recognition elements that were previously immobilized (‘spotted’) on a chip substrate. See, Ramsay, G., “DNA chips: State-of-the-art,” Nature Biotechnology 16(1): 40-44 (1998); Zhu, H., M. Bilgin, et al., “Global analysis of protein activities using proteome chips,” Science 293(5537): 2101-2105 (2001); MacBeath, G., “Protein microarrays and proteomics,” Nature Genetics 32: 526-532 (2002); and Zhu, H. and M. Snyder, “Protein chip technology,” Current Opinion in Chemical Biology 7(1): 55-63 (2003). The equilibrium intensity of the bound fluorescent biomarker is then compared to a threshold level to decide if an associated gene is either active or silent (Schena, Shalon et al. 1995). There are several major problems associated with this label-based detection scheme: First, it is often challenging to detect fluorescently labeled molecules against the background of excess fluorophore which can never be completely removed after chemical labeling. Second, the threshold for detection cannot be adjusted to accommodate for varying receptor affinities. Third, the need for target amplification and labeling can directly interfere with the analysis: amplification and labeling can change the original concentration of biomarkers, may not be practical for certain proteins or nucleic acids, and is an impediment for further automation of HT approaches in fully automated point-of-care testing (POCT) applications. And lastly, acquisition and analysis of the fluorescent image of the micro-array is technically involved and limits the use of the DNA chip technology as the analytic part of a small, portable, and robust lab-on-a-chip device.